Scientists Show Lack of Single Protein Results in Persistent Viral Infection

By Brandon Reynolds

Scientists from The Scripps
Research Institute have shown a single protein can make the difference between
an infection clearing out of the body or persisting for life. The results also
show where the defects occur in the immune system without the protein and offer
the possibility that targeting this signaling pathway could be beneficial for
treatment of persistent viral infections in humans. Currently hundreds of millions of people around the world
are afflicted with persistent viral infections such as HIV, HCV, and HBV.

The new study is published in the
June 14, 2012 issue of the journal Cell
Host & Microbe.

In the new study, a team led
by Scripps Research Professor Michael Oldstone showed what happened when a
mouse engineered without the protein TLR7 was infected with lymphocytic
choriomeningitis virus (LCMV), a virus employed to study the response of the
immune system to microbes. While normal mice infected with a LCMV variant
called Cl 13 could clear a persistent infection in 60 to 90 days,
TLR7-deficient mice were unable to purge the infection throughout their lives.

“It is well known that RNA
from many viruses, including influenza, HIV, and hepatitis C, induce signaling
through TLR7,” said Kevin Walsh, a research associate in Oldstone’s lab and the
first author of the study. “We demonstrated that TLR7 plays a significant role
in the generation of immune responses required to clear persistent LCMV infection.”

‘Biological Warfare’

In terms of the constant
biological warfare between host and microbes, the body is not so much a temple
as it is a medieval city. An infectious agent can invade through the skin or
mucosa, essentially scaling the walls. Once it’s inside it has to deal with the
body’s first responders, called Toll-like receptors (TLR). These receptors are
a pattern-recognition system to alert the immune system. TLRs form the first line of defense
specifically by recognizing molecules of the invading pathogen.

Ten TLRs have been identified in
humans. One of these, TLR7, is located inside the cell within endosomes and the
RNA of viruses are detected after they have entered the cell. “TLR7 is a very
important receptor in terms of viruses,” noted Oldstone.

In the current study, the
researchers chose to use LCMV to understand the role of TLR7. LCMV is,
according to Oldstone, “has been, and continues to be a Rosetta Stone to
explain basic concepts in immunology and virology.”

Once it was clear that the
absence of TLR7 compromised the immune system’s ability to clear LCMV
infection, Oldstone, Walsh, and their colleagues explored what was happening
downstream of the receptor.

Interestingly, the research
demonstrated that even when immune memory cells, which “learn” to fight an
infection and impart long-term immunity, were transferred from TLR7-sufficient
mice to TLR7-deficient mice, those deficient mice still couldn’t clear the
infection.

“The environment within
TLR7-deficient mice suppressed the ability of these memory cells to clear
the infection,” said Walsh.

Surprisingly Tired Cells

The team noticed several
unexpected things. First, in the
TLR7-deficient mice, there was a profusion of tired T cells. “You see more T
cells in TLR7-deficient mice early after infection, but they don't actually
clear the infection,” said Walsh. “Even though there were more of them, they
were less functional.” Second,
immune system B cells were severely hampered; specifically, the differentiation
and maturation of B cells to plasma cells, cells responsible for generating
antiviral antibody, was aborted.
Thus, both essential arms of the immune system, cellular and humoral,
required to clear viral infection were compromised.

Exhausted T cells produce fewer
molecules to attack and destroy infected cells. Exhaustion occurs in
TLR7-sufficient environments, too—but in those cases there is a resurrection of
the T cells 60 to 90 days following infection with LCMV Cl 13, which allows the
body to purge the virus. In the TLR7-deficient environment, this resurrection
never happens. The exhausted T cells linger, as does the infection. T cell
exhaustion is also found in HIV and hepatitis B and C infection.

“A number of phenomena that LCMV uses to cause a
persistent infection is the same that HIV, hepatitis C and B use,” said
Oldstone. “That's what makes our observation important. It means that if you understood what is
in the environment with loss of TLR7 signaling and how to correct that, you'd
have a better chance of treating those persistent human infections. We know how
to treat it in the mouse, and people are working very hard to do the treatments
in humans.”

In addition to Oldstone and Walsh, authors of the
paper, “Toll-like receptor 7 is required for effective adaptive immune
responses that prevent persistent virus infection,” were John R. Teijaro, Megan
J. Welch, Daniel M. Fremgen, and Karl von Tiehl of Scripps Research; Elina I.
Zuniga of the University of California, San Diego; Shawn D. Blackburn and E.
John Wherry of the University of Pennsylvania School of Medicine; and Richard
A. Flavell of Yale University. For more information, see http://www.cell.com/cell-host-microbe/abstract/S1931-3128(12)00163-1

This research was supported by the U.S. National
Institutes of Health.

Send comments to: press[at]scripps.edu

“If
you understood what is in the environment with loss of TLR7 signaling and how
to correct that, you'd have a better chance of treating those persistent human
infections [of HIV, and hepatitis C and B],” says Professor Michael Oldstone. (Photo by Kevin Fung.)

“We demonstrated that TLR7 plays a significant role in the
generation of immune responses required to clear persistent LCMV infection,” says
Research Associate Kevin Walsh.